title: Protection of dopaminergic neurons by 5-lipoxygenase inhibitor.
abstract: Neuroinflammation and oxidative stress are important factors that induce neurodegeneration in age-related neurological disorders. 5-Lipoxygenase (5-LOX) is the enzyme responsible for catalysing the synthesis of leukotriene or 5-HETE from arachidonic acid. 5-LOX is expressed in the central nervous system and may cause neurodegenerative disease. In this study, we investigated the effect of the pharmacological inhibition of 5-lipoxygenase on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/MPP(+)-induced dopaminergic neuronal death in midbrain neuron-glia co-cultures and in mice. It was found that 5-LOX was over-expressed in astrocytes after the injection of MPTP into C57BL6 mice. MK-886, a specific inhibitor of 5-LOX activating protein (FLAP), significantly increased [(3)H]-dopamine uptake, a functional indicator of the integrity of dopaminergic neurons, in midbrain cultures or the SH-SY5Y human dopaminergic cell line following MPP(+) treatment. In addition, LTB₄, one of 5-LOX's downstream products, was increased in the striatum and substantia nigra following MPTP injection in mice. LTB₄ but not LTD₄ and 5-HETE enhanced MPP(+)-induced neurotoxicity in primary midbrain cultures. MK-886 administration increased the number of tyrosine hydroxylase-positive neurons in the substantia nigra and the dopamine content in the striatum in MPTP-induced parkinsonian mice. Furthermore, the MPTP-induced upregulation of LTB₄ in the striatum and substantia nigra was antagonised by MK-886. These results suggest that 5-LOX inhibitors may be developed as novel neuroprotective agents and LTB₄ may play an important pathological role in Parkinson's disease.
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Kai-Hsiang
authors.initials: KH
authors.lastname: Kang
authors.forename: Horng-Hui
authors.initials: HH
authors.lastname: Liou
authors.forename: Mann-Jen
authors.initials: MJ
authors.lastname: Hour
authors.forename: Houng-Chi
authors.initials: HC
authors.lastname: Liou
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Fu
mesh_terms: D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000494:pharmacology*; D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D018920:Coculture Techniques; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000378:metabolism; D017998:Leukotriene D4 / Q000494:pharmacology; D020267:MPTP Poisoning / Q000503:physiopathology*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D002722:Chlorobenzenes
chemical_list: D058946:5-Lipoxygenase-Activating Protein Inhibitors; D058927:5-Lipoxygenase-Activating Proteins; D001094:Arachidonate 5-Lipoxygenase; D004298:Dopamine; D006893:Hydroxyeicosatetraenoic Acids; D007211:Indoles; D007975:Leukotriene B4; D017998:Leukotriene D4; D018696:Neuroprotective Agents; C060893:MK-886; D002722:Chlorobenzenes; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid
keywords: 5-Lipoxygenase; FLAP; MK-886; Parkinson's disease